An experimental drug combined with an already popular
memory-enhancing compound may further delay memory loss in
patients with Alzheimer's disease and other dementias,
Johns Hopkins University scientists, in collaboration with
researchers from the University of North Carolina, have
found.

The findings, described in the June issue of
Neuropharmacology, also indicate that the
experimental treatment in question — a compound known
as SGS742 — works by blocking certain chemicals that
interfere with memory formation.

"The findings in laboratory animals — both
improved memory in our tests and evidence that the drug
targets the biology for making memories in the brain
— places this drug on solid footing as a candidate
therapeutic agent," said the study's lead author,
Michela Gallagher.

SGS742, previously shown to improve memory in animals,
is an experimental treatment for memory disorders. It is
currently in human clinical trials led by California-based
Saegis Pharmaceuticals, which holds a worldwide exclusive
license granted by the drug's developer.

Gallagher, a Krieger-Eisenhower Professor and the
chair of the Department
of Psychological and Brain Sciences in the Krieger
School of Arts and Sciences, said these studies did not
address SGS742's potential as a cure or preventive
treatment for Alzheimer's disease itself. They were
intended, rather, to assess its potential as a treatment
for the disease's key symptom: memory loss.

"Memory impairment occurs early in the disease and
worsens as the disease progresses. However, until the later
stages of the disease, memory is impaired but not entirely
gone," Gallagher said. "By augmenting the brain's
memory-making ability, drugs could be used to treat this
symptom and to improve the quality of life for patients who
have a disease that has a slow progression over years."

SGS742 has been found in clinical trials to be
beneficial to humans with mild cognitive impairment. The
Johns Hopkins team investigated how the compound works. The
team compared SGS742 with Aricept (generic name:
donepezil), an approved and frequently used treatment for
Alzheimer's disease manufactured by Eisai. The Johns
Hopkins researchers found in animal studies that a
combination of SGS742 and Aricept improved memory to a
larger degree than either drug alone, implying a potential
for future combination therapy protocols.

The research team conducted this study on 60 normal
young male rats that were not memory-impaired. Each rat was
given at various times SGS742, Aricept, a combination of
the two drugs or no drugs at all, and was tested on its
skill navigating a series of mazes that placed increasing
demands on its memory.

"The mazes were designed to take advantage of the
rats' natural foraging instincts," said Rebecca Haberman,
an associate research scientist at Johns Hopkins who is a
co-author on the study. "Rats will not readily return to
the place where they previously ate all the available food.
So we asked the rats to remember where they had found
treats in the 'information' session, and to look for food
in new places during the recall tests."

It quickly became apparent that the rodents performed
better when they were given either SGS742 or Aricept rather
than no drug at all. What's more, those rats given both
SGS742 and Aricept were able to both acquire and retain
information more quickly and for a longer period of time
than when they had not been thus treated.

Researchers also analyzed the interaction of the
compound with the biological mechanisms involved in the
creation of long-term memory. They learned that SGS742
alters the activity of gene control machinery that is
important for memory consolidation.

They focused on a molecule, CREB2, that is believed to
block memory formation by binding to a specific gene
sequence. Analysis of the brains of the rats revealed that
those that had been treated with SGS742 had less CREB2
bound to this important gene sequence than did the rats
that had not been treated.

"This indicates that SGS742-treated rats had an easier
time activating the appropriate genes necessary for memory
consolidation," Haberman said. "The fact that SGS742
improved memory even when it was given after the rats were
exposed to information further supports that the drug is
important for retaining information and not just for
obtaining it."

Funding for this research was provided by Saegis
Pharmaceuticals. Authors on the paper from Johns Hopkins,
in addition to Haberman and Gallagher, are A. Helm and S.L.
Dean, also of the Department of Psychological and Brain
Sciences.

Gallagher is a scientific consultant to Saegis
Pharmaceuticals and has an equity interest in the company.
Under a licensing arrangement between Johns Hopkins and
Saegis, Gallagher is entitled to a share of royalties
received by the university on sales of products resulting
from this research.